The goal of this proposal is to generate forebrain neurons from human embryonic stem cells. Our general strategy is to sequentially expose ES cells to signals that lead to differentiation along a neuronal lineage, and to select for cells that display characteristics of forebrain neurons. These cells would then be used in transplantation experiments to determine if they are able to make synaptic connections with host neurons. If successful these experiments would provide a therapeutic strategy for the treatment of Alzheimer’s disease and other disorders that are characterized by loss of forebrain neurons. Currently there is no effective treatments for Alzheimer’s disease, and with an aging baby-boomer population, the incidence of this disease is likely to increase sharply. One of the few promising avenues to treat Alzheimer’s is the possibility of cell replacement therapy in which the neurons lost could be replaced by transplanted neurons. Embryonic stem cells, which have the ability to differentiate into various cells of the body, could be a key component of such a therapy if we can successfully differentiate them into forebrain neurons.

Statement of Benefit to California:

Alzheimer’s disease is a devastating sporadic neurological disorder that places all of us at risk. As the California population ages, there will be a significant increase in the incidence of Alzheimer’s disease, and the medical and financial cost on the state will be severe. There are currently no effective treatments for this disorder, and one of the few promises is the possibility of transplantation therapy to replace the neurons that are lost in the disease. Being able to generate forebrain neurons from human embryonic stem cells would provide a key tool in the fight against this disease. Needless to say, the development of an effective cell replacement therapy would not only be of immense medical significance as we care for our senior population, it will also greatly relieve the financial burden associated with the care of Alzheimer’s patients, which is often borne by the state.

Progress Report:

The goal of this proposal was to generate forebrain neurons from human embryonic stem cells. Our general strategy was to sequentially expose ES cells to signals that would lead the cells to acquire characteristics typical of differentiated brain cells that are lost in disorders such as Alzheimer's Disease. The most important advance of the research was our ability to achieve this goal. We now have a well-developed protocol that can be used to generate forebrain cells in culture. We have found that these cells not only express genes typical of these cells, they extend axons and dendrites and can make synaptic connections. These cells could be very useful for transplantation studies, as well as for developing cell culture models of Alzheimer's disease. Finally, we have discovered that the same protocol is effective in generating forebrain neurons from iPS cells, attesting to the general usefulness of this strategy.